Most immune responses occur only if a CD4 T lymphocyte recognizes foreign antigen in association with a self class II molecule of the major histocompatibility complex (MHC). According to the books, antigen presentation to CD4+ T cells involves antigen uptake into endocytic compartments where unfolded proteins meet with newly synthesized MHC class II molecules. Furthermore, these class II molecules are transported there directly by their association with the invariant chain. In contrast to this simplified view, the Section has discovered a multiplicity of pathways for class II-restricted antigen presentation. First, a new transport pathway for class II molecules to antigen processing compartments was described: a cohort of newly synthesized MHC class II molecules is transported directly to the cell surface, from where it is retrieved by a very efficient internalization signal in the cytoplasmic tail of the invariant chain. Interestingly, there is selectivity in this transport pathway: only class II molecules associated with the p33 form of the invariant chain are detected at the cell surface. Class II molecules associated with the p35 form of the invariant chain are transported directly to antigen processing compartments from the trans- Golgi. Second, a new pathway for the presentation of cytosolic proteins by class II molecules was identified. This endogenous pathway has been distinguished by genetic and biochemical approaches from the processing pathway for class I-restricted antigen presentation. In contrast to the class I pathway, this endogenous pathway for class II-restricted presentation involves only long-lived cytosolic antigen. Finally, several immunologically relevant antigens are presented by the recycling of mature cell surface MHC class II molecules. This pathway may be useful for the presentation of antigens that are rapidly degraded upon uptake into antigen-presentng cells.